The overall objective of Dr. O'Donnell's Genomic Epidemiology of Cardiovascular Disease research program during FY 2014 is to investigate the epidemiology and genetic/genomic epidemiology of subclinical and clinical atherosclerotic cardiovascular disease (CVD) and its risk factors, including hemostatic and thrombotic risk. The longer term goal is to translate these results to prediction, prevention and personalization of CVD medicine. The major projects have emanated from the SNP Health Association Resource (SHARe), the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium, and collaborative DNA and RNA sequencing projects. Dr. O'Donnell is the Associate Director of the NHLBI's Framingham Heart Study (FHS), Scientific Director and Steering Committee Chair of the NHLBI's Framingham Heart Study (FHS) SHARe Program, co-founder and Steering Committee Co-chair of the CHARGE Consortium, and Co-Director of the HeartGO Consortium of the NHLBI GO Exome Sequencing Project (ESP). Research Subjects: The research subjects consist primarily of participants of the Framingham Heart Study FHS original cohort, Offspring cohort and Generation 3, and secondarily of participants of several collaborating cohort studies. Phenotyping: Phenotyping consisted of: (a) risk factor measures from usual clinical exams (lipids, blood pressure, anthropometric and physical examination); (b) biomarkers from peripheral blood (eg, C-reactive protein, fibrinogen, von Willebrand factor); (c) imaging measures of subclinical atherosclerosis (coronary and abdominal and thoracic aortic atherosclerosis by multidetector CT imaging (MDCT) in 3500 Offspring and Generation 3 subjects; carotid intimal medial thickness (CIMT) and carotid plaque by B-mode ultrasonography in 3800 Offspring: aortic plaque, LV mass by cardiovascular magnetic resonance imaging (CMRI) in 1800); (d) clinical CVD outcomes (myocardial infarction; coronary heart disease; CVD) adjudicated by a physician endpoint validation committee; (e) gene expression of lymphocyte- and platelet-derived RNA using rtPCR, whole genome RNA profiling (Affymetrix Exon Array), and next-generation RNA sequencing. Genotyping in SHARe and resequencing: Genotyping derived from dense genomewide SNP scans including a 550K SNP scan (Affymetrix platform, 250K Nsp and 250K Sty and 50K gene-focussed MIP) in 9,400 FHS subjects from all three generations. Imputation of the 550K SNPs was conducted to 2.4 million HapMap SNPs using MACH and to 40 million SNPs from the 1000 Genomes Project. Additional SNP genotyping was conducted using various platforms including 250K functional exon variants on the exome chip (Illumina). Next-Generation sequencing including targeted gene region sequencing, whole exome sequencing, and whole genome sequencing, is being conducted in several US genome centers. Statistical association and linkage methods: Statistical association analyses of genomewide association (GWA) of genotypes with phenotypes were conducted using mixed linear and/or logistic regression, generalized estimating equations, and survival analyses, when appropriate; additionally, family based association testing. Statistical linkage analyses were conducted using SOLAR. Testing for association of low frequency variants and burden of rare variants was conducted using various tests. Replication Collaboration with the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium: To seek strong evidence for replication, we combined data within a consortium of prospective, observational cohort studies with genomewide SNP scans and a large, common set of phenotypes. In silico replication meta-analysis is performed. Research Accomplishments for Major Projects Directed by Dr. O'Donneell in FY 2014: 1. Bioinformatics Databases and Tools: Our group conducted comprehensive studies of a large database we compiled of >1400 genomewide association (GWA) studies through 2012. We published an overview of this database and made the database available via the CVEGH website. 2. Genetic determinants of valve calcium: In conjunction with the CHARGE Consortium, we followed up on our finding of LPA gene variants associated with aortic valve calcification and aortic stenosis to conduct Mendelian randomization experiments showing associations of LDL with valve calcium and aortic stenosis (manuscript submitted). 3. Genetic determinants of hemostatic factors and other biomarkers: In the CHARGE Consortium, we have completed an association study of exome chip variation with key hemostatic factors (manuscript in preparation). 4. Genetic determinants of subclinical atherosclerosis and risk factors: In conjunction with the CHARGE Consortium, we have completed 1000Genomes imputed GWA analysis of coronary artery calcification (in preparation) and carotid IMT (in preparation) as well as exome chip analysis of coronary calcification and carotid IMT (in preparation). 5. Genetic determinants of myocardial infarction/coronary heart disease: We contributed 1000Genomes imputed GWA analysis for the largest meta-analysis of coronary artery disease to date(in preparation). 6. Epidemiology of the risk of subclinical disease, metabolomics and genetics: In the CHARGE Consortium, we have completed a GWAS for incident MI (submitted). We are developing an updated Framingham CHD risk score that includes family history in the model (in preparation). We have submitted a papar on exome chip variation of metabolomic signatures in the Framingham Heart Study. Selected references (out of >50 publications published/in press in PubMed September 2013 to September 15 2014): 1: Tsao CW, ..., O'Donnell CJ, Mitchell GF. Cross-sectional relations of arterial stiffness, pressure pulsatility, wave reflection, and arterial calcification. Arterioscler Thromb Vasc Biol 2014 (epub ahead of print). 2: Keller MF, ..., O'Donnell CJ, Takahashi A, Wilson JG, Ganesh SK, Nalls MA. Trans-ethnic meta-analysis of white blood cell phenotypes. Hum Mol Genet 2014 (epub ahead of print). 3: Kraja AT, ..., O'Donnell CJ, Benjamin EJ, Alizadeh BZ, Prokopenko I, Meigs JB, Borecki IB. Pleiotropic genes for metabolic syndrome and inflammation. Mol Genet Metab 2014;112:317-338. 4: Bis JC, ..., O'Donnell CJ; CHARGE Subclinical Atherosclerosis Working Group. Sequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. Circ Cardiovasc Genet 2014;7:359-364. 5: Leslie R, O'Donnell CJ, Johnson AD. GRASP: analysis of genotype-phenotype results from 1390 genome-wide association studies and corresponding open access database. Bioinformatics 2014;30:i185-194. 6: Chuang ML, ..., O'Donnell CJ. Risk factor differences in calcified and noncalcified aortic plaque: the Framingham Heart Study. Arterioscler Thromb Vasc Biol 2014;34:1580-1586. 7: Huang J, ..., O'Donnell CJ. Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. Arterioscler Thromb Vasc Biol 2014;34:1093-1101. 8: Chuang ML, ..., O'Donnell CJ. Distribution of abdominal aortic calcium by computed tomography: impact of analysis method on quantitative calcium score. Acad Radiol 2013;20:1422-1428. 9: Zhang X, ..., O'Donnell CJ. Genetic associations with expression for genes implicated in GWAS studies for atherosclerotic cardiovascular disease and blood phenotypes. Hum Mol Genet 2014;2:782-795. 10: Sabater-Lleal M, ..., O'Donnell CJ. Multiethnic meta-analysis of genome-wide association studies in >100000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. Circulation 2013;128:1310-1324.